Pharmaceutical aerosol formulation

ABSTRACT

The present invention relates to novel pharmaceutical aerosol formulations comprising: (A) salmeterol xinafoate in the form of particles coated by spray-drying with at least one surfactant in the absence of any other coating excipient, in suspension in (B) a liquefied propellant gas which is 1,1,1,2,3,3,3-heptafluoro-n-propane or 1,1,1,2-tetrafluoroethane and mixtures thereof for administration particularly by the pulmonary route and to a process for preparing these formulations. It also relates to novel particles suitable for use in such formulations.

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/GB00/01418 filed 13 Apr. 2000 which claims priority fromGCC/P/99/126 filed 14 Apr. 1999 in Bahrain and GB9921289.6 filed 10 Sep.1999 in the United Kingdom.

The present invention relates to novel pharmaceutical aerosolformulations for the administration of salmeterol xinafoate particularlyby the pulmonary route and to a process for preparing theseformulations. It also relates to novel particles suitable for use insuch formulations.

The use of aerosols for the administration of medicaments by theperipheral aerial pathways has been known for several decades. Suchaerosols generally contain the therapeutic agent, one or more adjuvantssuch as solvents or surfactants and one or more propellants.

The most commonly used propellants in the past are chlorofluorocarbons,such as CCl₃F (Freon® 11), CCl₂F₂ (Freon® 12) or CF₂ClCF₂Cl (Freon®114). However, the recent phasing out of these propellant gases due totheir harmful effect on the ozone layer has caused manufacturers ofaerosol sprays to use new propellant gases which protect stratosphericozone.

Such “ozone-friendly” gases, also known as green gases, for exampleencompass hydrogen-containing chlorofluorocarbons, hydrogen-containingfluorocarbons and perfluorocarbons.

A specific group of therapeutic agents administered by the pulmonaryroute are antiasthmatics including bronchodilators andantiinflammatories of steroid type having a local therapeutic action inthe lungs and/or a systemic therapeutic action after absorption in theblood. 4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol was described as one of a wide rangeof bronchodilators in GB-A-2140800. This compound is also known by thegeneric name of salmeterol, the xinafoate salt of which has becomewidely known as a highly effective treatment of inflammatory diseases,such as asthma and chronic obstructive pulmonary disease (COPD).

For medicaments such as salmeterol xinafoate, the replacement of theusual chlorofluorocarbon propellants by the novel propellants whichprotect the ozone layer can be accompanied by problems of stability ofthe suspensions. This is because the change in the polarity of thepropellant sometimes results in a partial solubility of salmeterolxinafoate in the liquefied gas. This partial solubility may lead to anundesirable increase in the size of the particles during storage and/orthe formation of aggregates. Formulations of salmeterol xinafoate inhydrofluoroalkane (HFA) propellant are known to be susceptible toabsorption of the drug into the rubber components of the valves of theadministration device. This may then cause the valves to seize resultingin a reduction of fine particle mass and/or the aggregates of particleswill penetrate less well into the fine lower respiratory pathways,subsequently causing problems with dose uniformity.

International Patent Application No. WO 92/08446 (Glaxo Group Limited)discloses surfactant coated drug particles, however, such a formulationspecifically requires a co-solvent. European Patent Application No.EP-A-0 493437 (Riker Laboratories Inc) discloses the presence ofsurfactants in a pharmaceutical aerosol formulation, however, the use ofsalmeterol xinafoate in such a formulation is not described. EuropeanPatent No. EP-A-0 556239 (Glaxo Group Limited) discloses surfactantcoated medicaments, however, drying is performed by evaporation of thesolvent and the use of ‘spray-drying’ is not described. WO 94/03153(Glaxo Group Limited) discloses a suspension formulation ofbeclomethasone dipropionate, but specifically excludes the presence of asurfactant. WO 93/11743, WO 93/11744 and WO 93/11745 (Glaxo GroupLimited) also disclose suspension formulations of drugs whichspecifically exclude the presence of surfactant. WO 97/35562(Danbiosyst) describes a composition of spray dried medicaments,however, polysaccharides are incorporated and the use of surfactants insuch a composition is not described. EP-A-257915 (Innovata) alsodescribes a formulation comprising a spray-dried drug microcapsule,however, the use of salmeterol xinafoate in such a formulation is notdescribed; furthermore, there is no disclosure of their use informulations containing a liquefied propellant gas. WO 91/16882(Liposome Technology) discloses a process for spray drying adrug/lipid-containing ethanol solution, but there is no mention ofemploying a surfactant in this process. EP-A-655237 (Hoechst) disclosespressurised aerosol formulations containing spray-dried product, whereinthe spray-dried product is obtained by spray-drying a solution of drug,surfactant and (optionally) auxiliary substance to give a finelydispersed matrix, however, there is no mention of salmeterol xinafoate.International Patent Application Nos. WO 98/29096 and WO 98/29098(Inhale Therapeutic Systems) describe the use of spray-drying ahydrophilic component and a hydrophobic component (eg. lactose),optionally stabilised by a surfactant, to provide dry powders withuniform characteristics.

We have now discovered that it is possible to improve the stability ofsuspensions of salmeterol xinafoate in the propellant by providing thedrug particles with a spray-dried coating of surfactant in the absenceof any other coating excipient. This protective layer apparentlyprevents the partial solubilization of the drug in the propellant andthe formation of aggregates. It is thus possible to obtain aerosolformulations for pulmonary administration which, when protected fromatmospheric moisture, are stable for months and make it possible todeliver drug particles having sizes which are sufficiently small topenetrate into the respiratory pathways.

A first subject of the present invention is consequently apharmaceutical aerosol formulation comprising salmeterol xinafoate inthe form of particles coated by spray-drying with surfactant in theabsence of any other coating excipient in suspension in a liquefiedpropellant gas. A further subject of the present invention is theprocess for preparing these particles and pharmaceutical formulations. Astill further subject are the spray-dried coated salmeterol xinafoateparticdes. Further subjects will become apparent to those skilled in theart from the following description and examples.

The present invention thus provides a pharmaceutical aerosol formulationcomprising

-   -   (A) salmeterol xinafoate in the form of particles coated by        spray-drying with at least one surfactant in the absence of any        other coating excipient, in suspension in    -   (B) a liquefied propellant gas which is        1,1,1,2,3,3,3-heptafluoro-n-propane or 1,1,1,2-tetrafluoroethane        and mixtures thereof.

According to the present invention, the salmeterol xinafoate particlesare coated with at least one surfactant. This surfactant must bephysiologically acceptable when it is used by inhalation, it must alsobe insoluble (or essentially insoluble) in the liquefied propellant gasor gases and must not have affinity therewith.

Examples of surfactants which can be used according to the presentinvention are anionic surfactants such as oleic acid, non-ionicsurfactants such as sorbitan trioleate, sorbitan monooleate, sorbitanmonolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene(20) sorbitan monooleate (Polysorbate 80), natural lecithin, oleylpolyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, laurylpolyoxyethylene (4) ether, block copolymers of ethylene oxide and ofpropylene oxide, synthetic lecithin, diethylene glycol dioleate,tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glycerylmonooleate, glyceryl monostearate, glyceryl monoricinoleate, glycerylricinoleate 30 OE, glyceryl ricinoleate 60 OE, cetyl alcohol, stearylalcohol, polyethylene glycol 400 or glyceryl monolaurate, or cationicsurfactants, such as cetylpyridinium chloride or benzalkonium chloride.Other examples of surfactants include synthetic phosphatides eg.distearoylphosphatidylcholine.

Preferably a single surfactant will be used.

Use will preferably be made of lecithin, polyoxyethylene (20) sorbitanmonooleate (Polysorbate 80), sorbitan monolaurate, glyceryl ricinoleate30 OE and glyceryl ricinoleate 60 OE. Particularly preferred surfactantsinclude lecithin and sorbitan monolaurate. Lecithin is most especiallypreferred; sorbitan monolaurate is also especially preferred.

As indicated above the particles of salmeterol xinafoate are coated byspray-drying with at least one surfactant in the absence of any othercoating excipient. In particular the use of sugars as coating excipientsis avoided.

The propellant is preferably 1,1,1,2,3,3,3-heptafluoro-n-propane(HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), especially1,1,2-tetrafluoroethane.

The coated salmeterol xinafoate particles of the aerosol formulations ofthe present invention must have sizes which allow them to beadministered by inhalation. The particles must be sufficiently small, onthe one hand, to penetrate into the pulmonary pathways withoutencountering obstacles and, on the other hand, they must have asufficiently large size to deposit in the lung and not to be carriedaway by exhalation. The penetration of the salmeterol xinafoateparticles as far as the pulmonary bronchioli and alveoli is generallyonly considered possible for particles having a mean size of less than20 μm, preferably of less than 5 μm. The size of the spray-dried coatedsalmeterol xinafoate particles of the present invention is preferablywithin the range from 0.5 μm to 10 μm, in particular from 1 μm to 5 μm.

The pharmaceutical compositions according to the invention may alsocomprise other pharmaceutically acceptable ingredients such asco-solvents or surfactants. In a preferred embodiment of the presentinvention, the formulations contain no surfactant besides that coated onthe salmeterol xinafoate particles and no co-solvents.

The pharmaceutical compositions according to the invention may also beused in combination with other therapeutic agents, for exampleanti-inflammatory agents (such as corticosteroids (eg. fluticasonepropionate, beclomethasone dipropionate, mometasone furoate,triamcinolone acetonide, rofleponide or budesonide) or NSAIDs (eg.sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotrieneantagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2integrin antagonists and adenosine 2a agonists)) or other betaadrenergic agents (such as salbutamol, formoterol, fenoterol orterbutaline and salts thereof) or antiinfective agents (eg. antibiotics,antivirals).

According to the invention there is most preferred a pharmaceuticalaerosol formulation which consists of

-   -   (A) salmeterol xinafoate in the form of particles coated by        spray-drying with at least one surfactant in the absence of any        other coating excipient, in suspension in    -   (B) a liquefied propellant gas which is        1,1,1,2,3,3,3-heptafluoro-n-propane or 1,1,1,2-tetrafluoroethane        and mixtures thereof.

The present invention also provides a method for preparing apharmaceutical aerosol formulation which comprises coating saimeterolxinafoate particles by spray-drying with at least one surfactant in theabsence of any other coating excipient and in packaging them, togetherwith the propellant, in a pressurised cartridge.

The process for the preparation of the pharmaceutical aerosolformulation of the present invention comprises, more specifically, thestages which consist

-   -   (a) in preparing a suspension containing        -   salmeterol xinafoate in the form of particles,        -   a suspending medium which is a non-solvent for salmeterol            xinafoate, and        -   one or more surfactants dispersed in the suspending medium;    -   (b) in spray drying the suspension obtained in stage (a), so as        to obtain salmeterol xinafoate particles coated by spray-drying        with the surfactant(s);    -   (c) in suspending the coated salmeterol xinafoate particles        obtained in stage (b) in the liquefied propellant gas.

The particles of salmeterol xinafoate used in step (a) will also be ofsize suitable for inhalation eg. of mean size less than 20 μm (eg. 0.5μm–10 μm) preferably less than 5 μm (eg. 1 μm–5 μm).

In one embodiment of the process of the invention, the suspension ofstage (a) above is prepared by dispersing the surfactant(s) in the saidsuspending medium and by subsequently dispersing the salmeterolxinafoate particles in the suspension thus obtained.

It is also possible, according to another embodiment of the process ofthe invention, to adsorb, in a first step, the surfactant on theuncoated salmeterol xinafoate particles and subsequently to disperse theparticle/surfactant combination in the suspending medium.

The suspending medium used for coating of the salmeterol xinafoateparticles has to be essentially non solvent for the therapeutic agent(eg. where the solubility of salmeterol xinafoate in the suspendingmedium is less than around 0.1 mg/ml). The preferred suspending mediumis water. The content of salmeterol xinafoate in the suspension preparedin stage (a) can vary within wide limits. It is generally within therange from 1 to 40% (mass/volume), preferably in the range from 1 to20%, eg. 5% (mass/volume).

The content of surfactant in the suspension prepared in stage (a) isgenerally between 0.001 and 5% by weight, preferably between 0.001 and1% by weight.

When the content of salmeterol xinafoate in the suspension prepared instage (a) is around 5% (mass/volume) the content of surfactant in thedried product prepared in stage (b) is generally between 0.01 and 20% byweight, preferably between 0.05 and 10% by weight.

The suspension described above is subsequently subjected to spray dryingin an appropriate device. The suspension to be dried is dispersed asfine droplets in a stream of hot air, which instantaneously transformsthem into small grains of powder. A person skilled in the art would knowhow to adjust the operating parameters, such as the flow rate of thesuspension arriving in the drying chamber, the size of the nozzle, theinlet and outlet temperature, the atomising pressure and the flow rateof the atomising air, according to the recommendations of themanufacturer and as a function of the characteristics of the productwhich he desires to obtain.

A suitable spray dryer which makes possible the drying of the salmeterolxinafoate particles of the present invention is the Büchi 191 Mini SprayDryer (Büchi Company, Switzerland). Typical physical parameters of theatomisation in such a device which make it possible to obtain the coatedparticles of active principle from the suspension of stage (a) are asfollows:

Inlet air temperature: 105° C.

Outlet air temperature: 50–70° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 4–5 ml/min

wherein NL represents ‘normal liter’ i.e a liter of gas administered atnormal temperature (25° C.) and normal pressure (1 atmosphere).

The spray-dried material obtained is generally composed of particleshaving a mean size of between 1 μm and 10 μm and a water content ofbetween 0.01 and 0.5% by weight.

If necessary, the particles obtained by spray drying can be subjected tosize reduction eg. micronisation or to any other method which is able toreduce their mean size to a value of less than 10 μm and preferably ofless than 5 μm, before suspension in the propellant. Indeed, spraydrying may result in partial aggregation of the particles bound to eachother by the coating layer, this aggregation increasing substantiallythe apparent mean size of the particles. The main purpose of this stepis to break up these aggregates. It is optional and its usefulnessdepends, of course, on the presence of aggregates, in other words on thesize of the particles after spray drying.

Micronisation is carried out in devices known as compressed-airmicronisers or fluid jet mills. In these devices, the particles arecarried by a strong stream of air into a chamber designed so that theparticles are subjected therein to a large number of impacts. In orderto obtain coated salmeterol xinafoate particles having an appropriatesize, these devices will be made to operate at a pressure of between 6and 14 bar, preferably between 8 and 12 bar.

The cartridges may be filled by any means which makes it possible toobtain a homogeneous suspension of the coated salmeterol xinafoateparticles in the propellant. The cartridges can be filled, for example,first with the particles and then with the propellant (‘dual stage’) oralternatively with a prepared suspension of the particles in thepropellant (‘single stage’).

This filling will preferably be carried out in a controlled atmospherewith a low relative humidity, in order to limit the hydration of theparticles during filling.

Cartridges will generally be fitted with a metering valve and a metereddose inhaler (MDI) will comprise such a cartridge and valve togetherwith a channelling device suitable for delivery of the formulation tothe lung.

The cartridges are preferably but not necessarily stored in a packagingcomposed of a film which is impermeable to atmospheric moisture. Thesuspensions contained in these overwrapped cartridges are expected to bestable for several months at room temperature (25° C.). Other means toresist ingress of moisture to the canister may also be employed.

As a further aspect of the invention we present a process for thepreparation of a pharmaceutical aerosol formulation according to thepresent invention characterised in that it comprises overwrapping filledcartridges with a film which is impermeable to atmospheric moisture.

A further aspect of the invention is salmeterol xinafoate in the form ofparticles coated by spray-drying with at least one surfactant in theabsence of any other coating excipient suitable for use, in combinationwith a propellant gas, in a pharmaceutical aerosol formulation accordingto the present invention.

As a further aspect of the invention we present salmeterol xinafoate inthe form of particles coated by spray-drying with at least onesurfactant in the absence of any other coating excipient obtainable by aprocess which comprises the stages which consist

-   -   (a) in preparing a suspension containing        -   salmeterol xinafoate in the form of particles,        -   a suspending medium which is a non-solvent for salmeterol            xinafoate, and        -   one or more surfactants dispersed in the suspending medium;    -   (b) in spray drying the suspension of the active principle        obtained in stage (a), so as to obtain salmeterol xinafoate        particles coated by the surfactant(s).

Cartridges containing a formulation according to the present inventionalso form an aspect of the invention.

EXAMPLES

The following examples are intended to illustrate the invention but donot have a limiting nature.

Example 1

0.2 g of lecithin may be dissolved in 200 ml of demineralized water atroom temperature (20° C.±2° C.). 10 g of salmeterol xinafoate asmicronised particles may be dispersed under stirring in the lecithinaqueous solution. The suspension thus obtained contains 5% salmeterolxinafoate and 0.1% lecithin. This suspension may then be spray-dried ina Büchi 191 Mini Spray Dryer with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 58° C.

Compressed air pressure: 7 bars

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is around 70% (eg. 73%).

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained may be micronised in a fluid jet mill(MC 50, JET Pharma S.A.) under a pressure of 8 bars.

The characteristics of the particles before being placed in canistersare as follows:

mean diameter around 1.5 μm water content: 0.03% (w/w)

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 2

1 g of lecithin may be dissolved in 200 ml of demineralized water atroom temperature (20° C.±2° C.). 10 g of salmeterol xinafoate asmicronised particles may be dispersed under stirring in the lecithinaqueous solution. The suspension thus obtained contains 5% salmeterolxinafoate and 0.5% lecithin.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 61° C.

Compressed air pressure: 7 bars

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is 65%.

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The particles before being placed in canisters have a mean diameteraround 1.5 μm.

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 3

0.2 g of Montane 20 (sorbitan monolaurate) may be dissolved in 200 ml ofdemineralized water at room temperature (20° C.±2° C.). 10 g ofsalmeterol xinafoate as micronised particles may be dispersed understirring in the Montane 20-aqueous solution. The suspension thusobtained contains 5% salmeterol xinafoate and 0.1% Montane 20.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air-temperature: 105° C.

Outlet air temperature: 50° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is 69%.

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The characteristics of the particles before being placed in canistersare as follows:

mean diameter around 1.5 μm

water content: 0.02%

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 4

0.2 g of Montanox 80 (Polysorbate 80) may be dissolved in 200 ml ofdemineralized water at room temperature (20° C.±2° C.). 10 g ofsalmeterol xinafoate as micronised particles may be dispersed understirring in the Montanox 80 aqueous solution. The suspension thusobtained contains 5% salmeterol xinafoate and 0.1% Montanox 80.

This suspension is then spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 50° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is 75%.

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The particles before being placed in canisters have a mean diameteraround 1.5 μm.

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 5

0.2 g of Simulsol 5817 (glyceryl ricinoleate 30 OE) may be dissolved in200 ml of demineralized water at room temperature (20° C.±2° C.). 10 gof salmeterol xinafoate as micronised particles may be dispersed understirring in the Simulsol 5817 aqueous solution. The suspension thusobtained contains 5% salmeterol xinafoate and 0.1% Simulsol 5817.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 59° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is 78%.

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The particles before being placed in canisters have a mean diameteraround 1.5 μm.

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 6

0.2 g of Simulsol 1285 DF (glyceryl ricinoleate 60 OE) may be dissolvedin 200 ml of demineralized water at room temperature (20° C.±2° C.). 10g of salmeterol xinafoate as micronised particles may be dispersed understirring in the Simulsol 1285 DF aqueous solution. The suspension thusobtained contains 5% salmeterol xinafoate and 0.1% Simulsol 1285 DF.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature 58° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is 54%.

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The particles before being placed in canisters have a mean diameteraround 1.5 μm.

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 7

1 g of Montane 20 (sorbitan monolaurate) may be dissolved in 200 ml ofdemineralized water at room temperature (20° C.±2° C.). 10 g ofsalmeterol xinafoate as micronised particles may be dispersed understirring in the Montane 20 aqueous solution. The suspension thusobtained contains 5% salmeterol xinafoate and 0.5% Montane 20.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 53° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: 5 ml/min

The yield of the spray drying is 73%.

The water content of powder is less than 0.5% (w/w). The particlesbefore being micronised have a mean diameter between 2 and 5 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The particles before being placed in canisters have a mean diameteraround 1.5 μm.

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 8

0.5 g of Montane 20 (sorbitan monolaurate) may be dissolved in 99.5 mlof demineralized water at room temperature (20° C.±2° C.). Then 5 g ofthis solution are dissolved in 995 ml of demineralized water at roomtemperature. 20 g of salmeterol xinafoate as micronised particles arethen dispersed under stirring in 400 ml of this Montane 20 aqueoussolution. The suspension thus obtained contains 5% salmeterol xinafoateand 0.0025% Montane 20.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 60° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: around 4 ml/min

The yield of the spray drying is around 60%.*

The water content of powder is 0.02% (w/w). The particles before beingmicronised have a mean diameter of 2.4 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The characteristics of the particles before being placed in canistersare as follows:

mean diameter around 1.5 μm

water content: 0.02%

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 9

0.5 g of Montane 20 (sorbitan monolaurate) may be dissolved in 99.5 mlof demineralized water at room temperature (20° C.±2° C.). Then 10 g ofthis solution are dissolved in 990 ml of demineralized water at roomtemperature. 20 g of salmeterol xinafoate as micronised particles arethen dispersed under stirring in 400 ml of this Montane 20 aqueoussolution. The suspension thus obtained contains 5% salmeterol xinafoateand 0.005% Montane 20.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 60° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: around 4 ml/min

The yield of the spray drying is between 68 and 76%.

The water content of powder is 0.01% (w/w). The particles before beingmicronised have a mean diameter of 2.3 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The characteristics of the particles before being placed in canistersare as follows:

mean diameter around 1.3 μm

water content: 0.02%

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 10

5 g of Montane 20 (sorbitan monolaurate) may be dissolved in 95 ml ofdemineralized water at room temperature (20° C.±2° C.). Then 5 g of thissolution are dissolved in 995 ml of demineralized water at roomtemperature. 20 g of salmeterol xinafoate as micronised particles arethen dispersed under stirring in 400 ml of this Montane 20 aqueoussolution. The suspension thus obtained contains 5% salmeterol xinafoateand 0.025% Montane 20.

This suspension may then be spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 63° C.

Compressed air pressure 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: around 4 ml/min

The yield of the spray drying is around 77%.

The water content of powder is 0.02% (w/w). The particles before beingmicronised have a mean diameter of 2.4 μm.

The spray dried material obtained is micronised in a fluid jet mill (MC50, JET Pharma S.A.) under a pressure of 8 bars.

The characteristics of the particles before being placed in canistersare as follows:

mean diameter around 1.5 μm

water content: 0.02%

The canisters are filled manually in a controlled atmosphere room (20±2°C., relative humidity of less than 15%) by successively introducing themicronised material and then pressurised HFA134a gas.

Example 11

0.5 g of lecithin was dissolved in 99.5 ml of demineralized water atroom temperature. 5 g of this solution was then dissolved in. 995 ml ofdemineralized water at room temperature. 20 g of salmeterol xinafoate asmicronized particles were then dispersed under stirring in 400 ml ofthis lecithin aqueous solution. The suspension thus obtained contained5% salmeterol xinafoate and 0.0025% lecithin.

This suspension was then spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 61° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: around 4 ml/min

The yield of the spray drying was around 70%.

The water content of powder was 0.01% (w/w). The particles before beingmicronized had a mean diameter between 2 and 5 μm.

The spray dried material obtained was micronized in a fluid jet mill (MC50, company Jet Pharma) under a pressure of 8 bars.

The characteristics of the particles before being placed in canisterswere as follows:

mean diameter around 1.5 μm

water content: 0.01%

The canisters were filled manually in a controlled atmosphere room(20±2° C., relative humidity of less than 15%) by successivelyintroducing the micronized material and then pressurised HFA134a gas.

Example 12

5 g of lecithin was dissolved in 95 ml of demineralized water at roomtemperature. 5 g of this solution was then dissolved in 995 ml ofdemineralized water at room temperature. 20 g of salmeterol xinafoate asmicronized particles were then dispersed under stirring in 400 ml ofthis lecithin aqueous solution. The suspension thus obtained contained5% salmeterol xinafoate and 0.025% lecithin.

This suspension was then spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 60° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: around 4 ml/min

The yield of the spray drying was around 75%.

The water content of powder was 0.01% (w/w). The particles before beingmicronized had a mean diameter between 2 and 5 μm.

The spray dried material obtained was micronized in a fluid jet mill (MC50, company Jet Pharma) under a pressure of 8 bars.

The characteristics of the particles before being placed in canisterswere as follows:

mean diameter around 1.5 μm

water content: 0.01%

The canisters were filled manually in a controlled atmosphere room(20±2° C., relative humidity of less than 15%) by successivelyintroducing the micronized material and then pressurised HFA134a gas.

Example 13

5 g of lecithin was dissolved in 95 ml of demineralized water at roomtemperature. 10 g of this solution was then dissolved in 990 ml ofdemineralized water at room temperature. 20 g of salmeterol xinafoate asmicronized particles were then dispersed under stirring in 400 ml ofthis lecithin solution. The suspension thus obtained contained 5%salmeterol xinafoate and 0.05% lecithin.

This suspension, was then spray-dried in a Büchi 191 Mini Spray Dryeroperating with the following parameters:

Inlet air temperature: 105° C.

Outlet air temperature: 60° C.

Compressed air pressure: 7 bar

Atomising air flow rate: 800 NL/h

Drying air flow: 28 m³/h

Feed flow: around 4 ml/min

The yield of the spray drying was around 75%.

The water content of powder was 0.01% (w/w). The particles before beingmicronized had a mean diameter between 2 and 5 μm.

The spray dried material obtained was micronized in a fluid jet mill (MC50, company Jet Pharma) under a pressure of 8 bars.

The characteristics of the particles before being placed in canisterswere as follows:

mean diameter around 1.5 μm

water content: 0.01%

The canisters were filled manually in a controlled atmosphere room(20±2° C., relative humidity of less than 15%) by successivelyintroducing the micronized material and then pressurised HFA134a gas.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

1. A process for the preparation of a pharmaceutical aerosol formulationthat comprises: (A) salmeterol xinafoate in the form of particles havinga coating that comprises at least one surfactant, which surfactant isphysiologically acceptable when used by inhalation, in the absence ofany coating excipient that is a sugar, wherein the particles have awater content of between 0.01 and 0.5% by weight of the particles, insuspension in (B) a liquefied propellant gas which is1,1,1,2,3,3,3-beptafluoro-n-propane or 1,1,1,2-tetrafluoroethane ormixtures thereof, wherein the at least one surfactant is essentiallyinsoluble in the liquefied propellant gas and does not have an affinitytherewith; said process comprising: providing a suspension comprisingsalmeterol xinafoate in the form of particles, a suspending medium thatis water, and one or more surfactants; spray drying the suspensionproducing salmeterol xinafoate particles coated with one or moresurfactants; and, suspending the coated salmeterol xinafoate particlesin liquefied propellant.
 2. A process for the preparation of apharmaceutical aerosol formulation according to claim 1, furthercomprising reducing the size of the coated particles obtained by spraydrying before suspension in the propellant.
 3. A process for thepreparation of a pharmaceutical aerosol formulation according to claim1, wherein the mean size of the coated drug particles is within therange from 0.5 to 10 μm.
 4. A process for the preparation of apharmaceutical aerosol formulation according to claim 3, wherein themean size of the coated drug particles is within the range from 1 to 5μm.
 5. A process for the preparation of a pharmaceutical aerosolformulation according to claim 1, wherein the providing of thesuspension comprises: suspending salmeterol xinafoate in the form ofparticles in the suspending medium for salmeterol xinafoate; anddispersing one or more surfactants in the suspending medium.
 6. Aprocess for the preparation of a pharmaceutical aerosol formulationaccording to claim 1, wherein the providing of the suspension comprises:dispensing one or more surfactants in the suspending medium to produce acolloidal solution; and subsequently dispersing the salmeterol xinafoateparticles in the colloidal solution.
 7. A process for the preparation ofa pharmaceutical aerosol formulation according to claim 1, wherein thecontent of salmeterol xinafoate in the suspension is within the rangefrom 1 to 40% (mass/volume).
 8. A process for the preparation of apharmaceutical aerosol formulation according to claim 7, wherein thecontent of salmeterol xinafoate in the suspension is in the range from 1to 20% (mass/volume).
 9. A process for the preparation of apharmaceutical aerosol formulation according to claim 1, wherein thecontent of surfactant in the suspension is between 0.001 and 5% byweight.
 10. A process for the preparation of a pharmaceutical aerosolformulation according to claim 9, wherein the content of surfactant inthe suspension is between 0.001 and 1% by weight.
 11. A process for thepreparation of a pharmaceutical aerosol formulation according to claim1, wherein the suspending of the coated salmeterol xinafoate particlesin liquefied propellant comprises successively filling cartridges withthe spray-dried particles and then filling the cartridges with thepropellant.
 12. A process for the preparation of a pharmaceuticalaerosol formulation according to claim 1, further comprising fillingcartridges with the coated salmeterol xinafoate particles suspended inliquefied propellant.
 13. A process for the preparation of apharmaceutical aerosol formulation according to claim 11, furthercomprising overwrapping filled cartridges with a film impermeable toatmospheric moisture.
 14. A process for the preparation of a compositionthat comprises salmeterol xinafoate in the form of particles having acoating comprising at least one surfactant, which surfactant isphysiologically acceptable when used by inhalation, in the absence ofany coating excipient that is a sugar, wherein the particles have awater content of between 0.01 and 0.5% by weight of the particles, saidprocess comprising: preparing a suspension containing salmeterolxinafoate in the form of particles, a suspending medium which is watersand one or more surfactants dispersed in the suspending medium; andspray drying the suspension so as to obtain salmeterol xinafoateparticles coated by the surfactant(s).